The mechanisms of determinant-specific Ir gene control and of antigen recognition by immunocompetent cells (T and B lymphocytes) were explored at several levels in responses to myoglobin. Liver macrophages, pretreated with antigen and washed, were found to mediate Ir gene controlled presentation of selected antigenic determinants for T cell responses. Pretreatment of these cells with anti-Ia antibodies not only blocked this ability, but also induced suppression of responses by untreated cells. In vitro antibody responses to myoglobin were found to be under the same gene control, and to be T-cell and macrophage dependent. Myoglobin-specific receptors were isolated from T cells and shown to be distinct from immunoglobulin and able to bind myoglobin in the absence of Ia antigens. Monoclonal antibodies to myoglobin were prepared and their fine specificity for different determinants defined, in order to study their binding sites in comparison with the complementary sites on the antigen. Thus it is hoped to understand the complex genetically controlled regulatory interactions between T cell, B cells, and macrophages in the immune response and the biochemical nature of the several antigen-specific receptors involved.